Obesity has become one of the most pressing public health issues of the current century. Unfortunately, tackling the high incidence of obesity is proving to be extremely difficult. Recent evidence suggests the brains of obese individuals resemble those of people addicted to drugs of abuse, with alterations in dopaminergic neurotransmission, arguing that cessation of over eating may be as difficult as abstaining from drug use. Consequently, elucidating the neural circuits that are involved in both the drive to consume high calorie foods and drugs of abuse is extremely important in the development of therapeutic strategies in the treatment of obesity and drug addiction. The proposed experiments examine, using mouse genetic models, the direct action of two potent metabolic signaling proteins, leptin and orexin, on neurons of the ventral tegmental area (VTA) and their control of energy homeostasis and modulation of the reinforcing properties of food and cocaine. VTA dopaminergic neurons, projecting to forebrain structures such as the nucleus accumbens and prefrontal cortex, are involved in mediating many of the behavioral responses to drugs of abuse. Interestingly, evidence suggests that VTA dopamine neurons are excited by orexin and inhibited by leptin. Thus, these metabolic signals may act in the VTA to modulate energy homeostasis along with the seeking of both drug and natural food rewards. In Aim 1, lepr will be deleted from mouse VTA neurons, using the Cre-lox system, to test the necessity of lepr signalling while in aim 2, a lepr allele that can be selectively reactivated on a null lepr background in the VTA will be used to test the sufficiency of VTA leptin signalling in regulating energy homeostasis and the reinforcing properties of food and cocaine. In Aim 3, mice carrying a mutant orexin 1 receptor allele that can be reactivated in the VTA on an orexin 1 receptor null background, similar to the leptin reactivatable receptor model, will be used to test the sufficency of orexin action in the VTA in modulating both energy homeostasis and the reinforcing properties of food and cocaine. In summary, the proposed studies will comprehensively test the action of orexin and leptin in the VTA and their subsequent effect on the development of obesity and the drive to consume both food and the psychostimulant cocaine. PUBLIC HEALTH RELEVANCE: The proposed studies will greatly increase our understanding of the mechanisms underlying drug addiction and the drive to consume calorie dense food. The study findings will provide valuble information with which to develop treatment strategies for the prevention of drug use and consumption of calorie dense food.